U.S. patent number 6,723,343 [Application Number 10/084,682] was granted by the patent office on 2004-04-20 for pharmaceutical tramadol salts.
This patent grant is currently assigned to Gruenenthal GmbH. Invention is credited to Heinrich Kugelmann.
United States Patent |
6,723,343 |
Kugelmann |
April 20, 2004 |
Pharmaceutical tramadol salts
Abstract
Disclosed are a compound of tramadol and a sugar substitute,
pharmaceutical compositions and sustained-release formulations
comprising the compound, and methods of treatment using the
compound. The tramadol compound according to the present invention
has reduced bitter taste of tramadol and is more acceptable to the
patient.
Inventors: |
Kugelmann; Heinrich (Aachen,
DE) |
Assignee: |
Gruenenthal GmbH (Aachen,
DE)
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Family
ID: |
7919846 |
Appl.
No.: |
10/084,682 |
Filed: |
February 28, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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PCTEP0007526 |
Aug 3, 2000 |
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Foreign Application Priority Data
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Aug 31, 1999 [DE] |
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199 40 740 |
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Current U.S.
Class: |
424/479; 424/465;
424/48; 424/490; 514/222.2; 514/373; 424/493 |
Current CPC
Class: |
A61K
31/135 (20130101); A61P 37/08 (20180101); A61K
31/205 (20130101); A61P 9/00 (20180101); C07D
275/06 (20130101); C07C 307/02 (20130101); A61P
1/00 (20180101); A61K 9/2081 (20130101); A61P
39/00 (20180101); A61P 25/24 (20180101); A61P
29/00 (20180101); C07C 217/74 (20130101); A61K
9/2846 (20130101); A61K 9/5047 (20130101); A61K
31/54 (20130101); A61P 13/00 (20180101); A61P
25/32 (20180101); A61K 31/428 (20130101); A61P
1/12 (20180101); A61P 25/30 (20180101); A61P
11/14 (20180101); A61P 1/04 (20180101); A61P
25/00 (20180101); A61P 25/08 (20180101); A61P
11/00 (20180101); A61P 25/18 (20180101); A61K
9/5026 (20130101); A61P 25/04 (20180101); A61P
13/02 (20180101); C07D 291/06 (20130101); A61P
25/36 (20180101); A61P 37/00 (20180101); C07C
2601/14 (20170501); A61K 9/006 (20130101); A61K
9/0095 (20130101); A61K 9/0056 (20130101); A61K
9/0058 (20130101) |
Current International
Class: |
A61K
31/135 (20060101); A61K 9/28 (20060101); A61K
31/205 (20060101); A61K 9/50 (20060101); A61K
9/20 (20060101); A61K 31/54 (20060101); A61K
31/185 (20060101); C07D 291/00 (20060101); C07D
291/06 (20060101); C07C 217/00 (20060101); C07C
217/74 (20060101); C07C 307/00 (20060101); C07C
307/02 (20060101); A61K 31/428 (20060101); C07D
275/06 (20060101); C07D 275/00 (20060101); A61K
9/00 (20060101); A61K 009/36 () |
Field of
Search: |
;424/479,490,493,465,48
;514/222.2,373 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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0144960 |
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Jun 1985 |
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EP |
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98/46216 |
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Oct 1998 |
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WO |
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00/12067 |
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Mar 2000 |
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WO |
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Other References
Buschann et al, Derwent abstract 2001-597702, 2/200..
|
Primary Examiner: Reamer; James H
Attorney, Agent or Firm: Crowell & Moring LLP
Parent Case Text
CROSS REFERENCE TO RELATED APPLICATIONS
The present application is a continuation of international patent
application no. PCT/EP00/07526, filed Aug. 3, 2000, designating the
United States of America, the entire disclosure of which is
incorporated herein by reference. Priority is claimed based on
Federal Republic of Germany patent application no. 199 40 740.1,
filed Aug. 31, 1999.
Claims
We claim:
1. A pharmaceutically acceptable salt of tramadol and a sugar
substitute, wherein the solubility of the salt in water or aqueous
body fluids is <100 mg/ml.
2. A salt according to claim 1, wherein the solubility is
.ltoreq.30 mg/ml.
3. A salt according to claim 2, wherein the solubility is
.ltoreq.10 mg/ml.
4. A salt according to claim 1, wherein the sugar substitute is
saccharin, cyclamate or acesulfame.
5. A pharmaceutical composition comprising a salt according to
claim 1, and a pharmaceutically acceptable excipient.
6. A method for the treatment of one or more of pain, urinary
incontinence, coughs, inflammatory and allergic reactions,
depression, drug and alcohol abuse, gastritis, diarrhea,
cardiovascular disease, respiratory disease, mental illness and
epilepsy, comprising administering an effective amount of the
pharmaceutical composition according to claim 5 to a patient in
need thereof.
7. A method according to claim 6, wherein the method is for the
control of pain.
8. A method according to claim 6, wherein the method is for the
treatment of urinary incontinence.
9. A method according to claim 6, wherein the method is for the
treatment of coughs.
10. A method according to claim 6, wherein the method is for the
treatment of inflammatory and allergic reactions.
11. A method according to claim 6, wherein the method is for the
treatment of depression.
12. A method according to claim 6, wherein the method is for the
treatment of drug and/or alcohol abuse.
13. A method according to claim 6, wherein the method is for the
treatment of gastritis.
14. A method according to claim 6, wherein the method is for the
treatment of diarrhea.
15. A method according to claim 6, wherein the method is for the
treatment of cardiovascular disease.
16. A method according to claim 6, wherein the method is for the
treatment of respiratory disease.
17. A method according to claim 6, wherein the method is for the
treatment of mental illness.
18. A method according to claim 6, wherein the method is for the
treatment of epilepsy.
19. A pharmaceutical composition according to claim 5, further
comprising an additional active substance.
20. A pharmaceutical composition according to claim 5, wherein the
pharmaceutical composition is a multiparticulate formulation.
21. A pharmaceutical composition according to claim 20, wherein the
multiparticulate formulation is selected from the group consisting
of granules, microparticles, microtablets and pellets.
22. A pharmaceutical composition of claim 21, wherein the
pharmaceutical composition is filled into capsules or in the form
of tablets, rapidly disintegrating tablets or effervescent tablets,
or in the form of pellets compressed to tablets.
23. A pharmaceutical composition of claim 22, wherein the
pharmaceutical composition comprises at least one enteric
coating.
24. A pharmaceutical composition of claim 21, wherein the
pharmaceutical composition is formulated as a gel, a chewing gum, a
juice or a spray.
25. A pharmaceutical composition of claim 24, wherein the spray is
a sublingual spray.
26. A pharmaceutical composition of claim 21, wherein the
pharmaceutical composition comprises at least one sustained-release
matrix.
27. A pharmaceutical composition of claim 21, wherein the
pharmaceutical composition comprises at least one sustained-release
coating.
28. A pharmaceutical composition of claim 24, wherein the juice is
an oil-based juice.
29. A pharmaceutical composition of claim 24, wherein the juice is
a water-based juice.
Description
BACKGROUND OF THE INVENTION
The present invention relates to pharmaceutical salts of the active
substance tramadol and at least one sugar substitute, to
medicaments, or pharmaceutical compositions, containing these
salts, to the use of these salts for the preparation of
medicaments, and to forms of administration or pharmaceutical
formulations, containing these salts.
Tramadol
hydrochloride--(1RS,2RS)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cycl
ohexanol hydrochloride--is suitable for the control of intense and
moderately intense pain and for the treatment of urinary
incontinence. U.S. Pat. No. 3,652,589 and WO98/46216 describe the
use of other salts of the active substance tramadol with inorganic
acids, e.g. sulfuric acid, nitric acid or phosphoric acid, and with
organic acids, e.g. benzoic acid, salicylic acid or phthalic acid,
for the preparation of a medicament for the control of pain or for
the treatment of urinary incontinence.
Despite the excellent efficacy of said salts in pain control, the
active substance tramadol and its readily soluble salts have an
intensely bitter taste. Available formulations of tramadol that
releases this active substance as soon as they are taken all have
this strong bitter taste. As a consequence, these immediate-release
formulations are poorly accepted and patients fail to observe the
dosage instructions. Although coating and complexing processes,
e.g. the application of film coatings, serve to improve taste, they
impede the immediate release of the active substance.
Because of the very good water solubility of tramadol
hydrochloride, the preparation of sustained-release pharmaceutical
forms is also made difficult. Consequently, it is necessary to use
complex retardation processes, e.g. the application of
sustained-release coatings or the embedding of the active substance
in a sustained-release matrix.
SUMMARY AND DETAILED DESCRIPTION OF THE INVENTION
The object of the present invention was therefore to provide
pharmaceutical compounds for the active substance tramadol which do
not have the bitter taste of tramadol and the release of which can
be retarded more effectively than that of the conventional, most
widely used salt, namely tramadol hydrochloride.
According to the invention, this object is achieved by the
preparation of pharmaceutical salts of the active substance
tramadol and at least one sugar substitute.
The solubility of these salts in water and/or aqueous fluids is
preferably .ltoreq.100 mg/ml, more preferably .ltoreq.30 mg/ml and
particularly preferably .ltoreq.10 mg/ml.
Suitable sugar substitutes are any acidic sugar substitutes which,
by producing a derivative carrying at least one negative charge,
are capable of forming a salt with the active substance tramadol.
The sugar substitute is preferably saccharin, cyclamate, acesulfame
or a mixture of at least two of these sugar substitutes.
To prepare the pharmaceutical salts according to the invention,
tramadol and/or at least one very readily water-soluble salt of
tramadol is reacted with at least one free acid and/or at least one
water-soluble salt of at least one sugar substitute. Said salt of
tramadol is preferably reacted with the water-soluble salt of the
sugar substitute in an aqueous medium at neutral pH. Tramadol
hydrochloride is preferably used as the salt of tramadol. The salt
of the sugar substitute used is preferably the sodium, potassium,
calcium or ammonium salt of saccharin and/or cyclamate and/or
acesulfame. The free acid of the sugar substitute used is
preferably the free acid of saccharin and/or cyclamate and/or
acesulfame. If tramadol itself is reacted with the free acid of a
sugar substitute, they are reacted in an organic solvent,
preferably in an alkanol and more preferably in ethanol.
The invention also provides medicaments or pharmaceutical
compositions which contain at least one tramadol salt according to
the invention as the pharmaceutical active substance, and
optionally other active substances and/or auxiliary substances.
The medicaments are preferably used for the control/treatment of
pain, urinary incontinence, coughs, inflammatory and allergic
reactions, depression, drug and/or alcohol abuse, gastritis,
diarrhoea, cardiovascular disease, respiratory disease, mental
illness and/or epilepsy.
The invention also provides the use of at least one tramadol salt
according to the invention for the preparation of a medicament for
the control/treatment of pain, urinary incontinence, coughs,
inflammatory and allergic reactions, depression, drug and/or
alcohol abuse, gastritis, diarrhoea, cardiovascular disease,
respiratory disease, mental illness and/or epilepsy.
The amount of active substance to be administered to the patient
varies according to the patient's weight, the type of
administration, the indication and the degree of severity of the
disease. Conventionally, at least one tramadol salt according to
the invention is administered in amounts in which the content of
the active substance tramadol corresponds to 1 to 600 mg/day.
The invention also provides for pharmaceutical formulations
containing at least one tramadol salt according to the
invention.
The amounts of tramadol and sugar substitute in the pharmaceutical
compositions or formulations according to the invention are to be
chosen so that the bitter taste of the active substance tramadol is
compensated by the taste of the sugar substitute. The forms of
administration according to the invention preferably contain the
sugar substitute and the tramadol in equimolar amounts, i.e. the
two components are virtually completely in salt form. The forms of
administration according to the invention can also contain the
tramadol and sugar substitute in different molar amounts according
to the sweetness of the sugar substitute used and/or the desired
release profile for the tramadol.
The forms of administration according to the invention can be
solid, semisolid or liquid, preferably oral medicament formulations
which, in addition to the salt of the active substance tramadol and
at least one sugar substitute, optionally contain other active
substances and the conventional auxiliary substances, excipients
and additives.
The solid forms of administration according to the invention are
preferably multiparticulate formulations, particularly preferably
in the form of granules, microparticles, microtablets or pellets
and optionally filled into capsules or in the form of tablets,
preferably rapidly disintegrating tablets or effervescent tablets,
the tablets preferably having been compressed from pellets or
produced by hot-melt extrusion.
If the solid forms of administration according to the invention are
intended for release of the active substances via the intestinal
tract, they preferably need to have at least one enteric coating
which dissolves as a function of pH. Because of this coating, said
forms pass through the stomach undissolved and the active
substance(s) is (are) only released in the intestinal tract.
The forms of administration according to the invention are also
preferably formulated as a gel, a chewing gum, a juice,
particularly preferably an oil-based or water-based juice, or a
spray, particularly preferably a sublingual spray.
A preferred embodiment of the forms of administration according to
the invention, for release of the tramadol via the stomach,
comprises oil-based or water-based juices, which release the active
substance(s) without delay.
A retardation and hence also a further modification of the release
of the active substance tramadol, and optionally other active
substances, can be effected by the application of at least one
sustained-release coating, the embedding of the salt of the active
substance in at least one sustained-release matrix, or a
combination thereof.
Retardation of release is preferably achieved with the aid of
sustained-release coatings. Suitable sustained-release coatings
include water-insoluble waxes or polymers, e.g. acrylic resins,
preferably poly(meth)acrylates, or water-insoluble celluloses,
preferably ethyl cellulose. These materials are well-known to those
of ordinary skill in the art. See, e.g. Bauer, Lehmann, Osterwald,
Rothgang "Uberzogene Arzneiformen" ("Coated pharmaceutical forms"),
Wissenschaftliche Verlagsgesellschaft mbH Stuttgart, 1988, pp. 69
et seq., which is incorporated herein by reference.
To adjust the rate of release of the active substance, the
sustained-release coatings can optionally contain, in addition to
the water-insoluble polymers, non-retarding, preferably
water-soluble polymers in amounts of up to 30 wt. %, such as
polyvinylpyrrolidone or water-soluble celluloses, preferably
hydroxypropyl methyl cellulose or hydroxypropyl cellulose, and/or
hydrophilic pore-forming agents such as sucrose, sodium chloride or
mannitol, and/or the known plasticizers.
To retard the salt of the active substance, the forms of
administration according to the invention can also preferably
contain said salt in a sustained-release matrix, preferably as a
uniform distribution.
Matrix materials which can be used are physiologically compatible,
hydrophilic materials known to those skilled in the art.
Hydrophilic matrix materials used are preferably polymers and
particularly preferably cellulose ethers, cellulose esters and/or
acrylic resins. Matrix materials used are very particularly
preferably ethyl cellulose, hydroxypropyl methyl cellulose,
hydroxypropyl cellulose, hydroxymethyl cellulose, poly(meth)acrylic
acid and/or derivatives thereof such as their salts, amides or
esters.
Other preferred matrix materials are those comprising hydrophobic
materials such as hydrophobic polymers, waxes, fats, long-chain
fatty acids, fatty alcohols or corresponding esters or ethers, or
mixtures thereof. The hydrophobic materials used are particularly
preferably C.sub.12 -C.sub.30 fatty acid mono- or diglycerides
and/or C.sub.12 -C.sub.30 fatty alcohols and/or waxes, or mixtures
thereof.
The sustained-release matrix material used can also be mixtures of
said hydrophilic and hydrophobic materials.
The forms of administration according to the invention can be
produced by various methods known to those skilled in the art, See,
e.g. "Pharmaceutical Pelletization Technology", Drugs and the
Pharmaceutical Sciences vol. 37, Verlag Marcel Decker, or
"Remington's Pharmaceutical Sciences", Mack Publishing Company,
Easton, Pa., which are herein incorporated by reference.
If the forms of administration according to the invention, e.g.
tablets or pellets, have coatings, these can be applied by
conventional processes, e.g. by the coating pan process, by the
spraying of solutions, dispersions or suspensions, by the hot-melt
process or by the powder application process.
From forms of administration according to the invention which are
used to release the tramadol via the oral mucosa, e.g. from a gel,
a chewing gum or a sublingual spray, a substantially constant
release of the tramadol is achieved without the use of a
sustained-release matrix and/or a sustained-release coating.
From forms of administration according to the invention which are
used to release the tramadol via the intestinal tract, e.g. from
capsules, tablets, granules or pellets, a constant release of the
tramadol is again achieved without the use of a sustained-release
matrix and/or a sustained-release coating, but with the provision
of an enteric coating.
The forms of administration according to the invention also have
the advantage that the intensely bitter taste of tramadol is
mitigated by the simultaneous release of a sugar substitute. This
increases the patients' acceptance of the medicaments containing
the active substance tramadol and improves observance of the dosage
instructions.
The medicaments according to the invention are also suitable for
diabetics.
The formation of a salt from tramadol and a sugar substitute and/or
an auxiliary substance with a solubility of .ltoreq.100 mg/ml in
water and/or aqueous body fluids affords a more effective
retardation of the release of the active substance tramadol using
conventional retardation processes, compared with tramadol
hydrochloride.
Sustained-release medicaments which contain these tramadol salts
according to the invention can therefore be produced more simply
and more cost-effectively. This also applies to other modifications
of the medicaments according to the invention, e.g. those with
enteric coatings.
The solubility of the salts of tramadol and a sugar substitute was
determined as follows:
The salt of
(1RS,2RS)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol
and the appropriate sugar substitute was placed at 25.degree. C. in
deionized water in an amount (e.g. approx. 1 g of tramadol
saccharinate to 10 ml of deionized water) to form a saturated
solution at this temperature which was still saturated after being
stirred for 20 hours at 25.degree. C. The requisite amount of the
salt of tramadol and the appropriate sugar substitute can
optionally be determined by preliminary experiments.
After the undissolved salt of tramadol and the appropriate sugar
substitute had been allowed to settle out, the clear supernatant
was pipetted off and centrifuged for 5 minutes at a speed of at
least 3000 rpm. Part of the resulting clear supernatant is
transferred to an HPLC sample vial and the concentration of the
salt of tramadol and the appropriate sugar substitute is determined
against tramadol hydrochloride as standard.
The invention is illustrated below with the aid of the Examples.
The illustrations are given solely by way of example and do not
limit the general spirit of the invention.
EXAMPLE 1
To prepare tramadol saccharinate, 30.0 g (0.1 mol) of tramadol
hydrochloride and 20.53 g (0.1 mol) of saccharin sodium or 24.13 g
(0.1 mol) of saccharin sodium dihydrate were completely dissolved
in the minimum amount of water, with heating in both cases. The two
solutions were then mixed together, with stirring. On cooling, the
tramadol saccharinate crystallized out of the aqueous solution
after only a short time and was isolated by conventional methods
and purified with ethanol.
The solubility of the resulting tramadol saccharinate in water was
determined by the method indicated above and is 22.5 mg/ml.
EXAMPLE 2
30.0 g (0.1 mol) of tramadol hydrochloride were dissolved in 20 g
of water and mixed slowly with a solution of 20.13 g (0.1 mol) of
sodium cyclamate in 36 g of water, with stirring. The resulting
solution was then stored for 16 hours at a temperature of 5.degree.
C. The tramadol cyclamate was obtained in crystalline form,
isolated by conventional methods and purified with ethanol.
EXAMPLE 3
30.0 g (0.1 mol) of tramadol hydrochloride were dissolved in 13 g
of water and mixed slowly with a solution of 20.13 g (0.1 mol) of
acesulfame potassium in 53 g of water, with stirring. The resulting
solution was then stored overnight at 5.degree. C. The tramadol
acesulfamate was obtained in crystalline form, isolated by
conventional methods and purified with ethanol.
EXAMPLE 4
An oral gel was prepared by first dissolving 0.33 g of
methylparaben, 0.05 g of propylparaben and 75.0 g of xylitol in
197.63 g of purified water at a temperature of 80.degree. C. and
then cooling the mixture to 40.degree. C. 0.75 g of tramadol
saccharinate was then added, with stirring, followed by 2 g of
xanthan gum, the mixture was stirred for a further one hour and
water lost by evaporation was replaced. After cooling to room
temperature, the mixture was flavoured with 0.625 g of
Orange-Mandarin Flavor 10888-56 (Givaudan Roure Flavors Ltd., CH
8600 Duibendorf, Germany), with stirring.
EXAMPLE 5
5 g of comminuted chewing gum mass (Popeye Amural Confections,
Yorkville, Ill.) were heated to a temperature of 30 to 40.degree.
C. in a Fanta dish. Using a pestle, 150 mg of tramadol saccharinate
were then incorporated into the viscous chewing gum mass. The
homogeneous mass was then divided up into 1 g portions in
teflon-coated moulds.
For a comparative taste test, chewing gums were prepared by the
same process with the stoichiometrically equivalent amount of
tramadol (corresponding to 100 mg of tramadol hydrochloride).
The result of the taste test was that the chewing gums containing
the tramadol hydrochloride had an intolerably bitter taste after
only a short time and could not be chewed any longer. The chewing
gums containing the tramadol saccharinate had an excellent taste at
the beginning and were still enjoyable even after prolonged
chewing.
EXAMPLE 6
To prepare a water-based juice, 0.33 g of methylparaben, 0.05 g of
propylparaben and 75.0 g of xylitol were dissolved in 198.37 g of
purified water at a temperature of 80.degree. C. The mixture was
cooled to 40.degree. C. and 0.75 g of tramadol saccharinate was
added, with stirring. 0.25 g of xanthan gum was then added, the
mixture was stirred for an addition hour and water lost by
evaporation was replaced. After cooling to room temperature, the
mixture was flavored with 0.075 g of Tutti Frutti 9/008897 (Dragoco
Gerberding & Co. AG, 37603 Holzminden, Germany), with
stirring.
EXAMPLE 7
To prepare an oil-based juice, 0.33 g of methylparaben and 0.05 g
of propylparaben were dissolved at a temperature of 80.degree. C.
in 209.88 g of glycerol esterified with saturated C.sub.8-10 fatty
acids. The mixture was cooled to 25.degree. C. and 37.5 g of ground
xylitol, 1.25 g of highly disperse silicon dioxide and 0.75 g of
tramadol saccharinate were suspended therein, with stirring. The
mixture was then flavored with 0.0125 g of Blood Orange 9/028658
(Dragoco Gerberding & Co. AG, 37603 Holzminden, Germany), with
stirring.
EXAMPLE 8
A sublingual spray was prepared by first dissolving 0.33 g of
methylparaben, 0.05 g of propylparaben and 75.0 g of xylitol in
197.37 g of distilled water at a temperature of 80.degree. C. The
solution was cooled to 40.degree. C. and 0.75 g of tramadol
saccharinate was added. 0.15 g of xanthan gum was then added, the
mixture was stirred for an additional hour and water lost by
evaporation was replaced. The solution was cooled to 25.degree. C.
and flavored with 0.75 g of Grapefruit 14391786 (IFF, International
Flavors & Fragrances GmbH, 46446 Emmerich, Germany).
The foregoing description and examples have been set forth merely
to illustrate the invention and are not intended to be limiting.
Since modifications of the described embodiments incorporating the
spirit and substance of the invention may occur to persons skilled
in the art, the invention should be construed broadly to include
all variations falling within the scope of the appended claims and
equivalents thereof.
* * * * *